A new stereoselective approach to aminocyclohexitols using RCM

Article abstract of DOI:10.1016/j.tetasy.2011.07.009

A new stereoselective approach for the synthesis of carbamannopyranosylamine and epi-valiolamine by using stereoselective allylation on lactamine and RCM from d-ribose has been described.

Full text of DOI:10.1016/j.tetasy.2011.07.009

Tetrahedron: Asymmetry 22 (2011) 1306–1311
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A new stereoselective approach to aminocyclohexitols using RCM
⇑
Anugula Rajender, Jalagam Prasada Rao, Batchu Venkateswara Rao
Organic division III, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new stereoselective approach for the synthesis of carbamannopyranosylamine and epi-valiolamine by
Received 16 May 2011
Accepted 12 July 2011
Available online 10 August 2011
using stereoselective allylation on lactamine and RCM from
D-ribose has been described.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
sor, and the amino group was generated from the nucleophilic
addition onto a ribosylamine.
Carbasugars1 are analogues of monosaccharides, in which the
ring oxygen is replaced with a methylene group. Similarly amino-
carbasugars are carbasugars in which the C-1 hydroxy is replaced
with an amino group; these compounds are generally glycosidase
inhibitors.2 Glycosidases are involved in several metabolic path-
ways, and the development of inhibitors for glycosidases is an
important challenge toward the treatment of diseases, such as dia-
betes, cancer, viral infections, and lysosomal storage disorder.3 Six
membered aminocarbasugars (aminocyclohexitols) are found in
Nature as part of complex molecules arising from the secondary
metabolism of several microorganisms; examples include valien-
amine 1, validamine 2, and valiolamine 3 (Fig. 1). Valiolamine 3
possesses very potent activity against maltase and sucrase. Chem-
ical modification of this compound has led to voglibose 4, which is
presently used for the treatment of diabetes.4 Different types of
validamine analogues have been prepared and tested with regard
to their glycosidase inhibitory activity.5 In these types of
compounds, the amino group mimics the protonated form of the
2. Results and discussion
Herein we report the application of our aforementioned strat-
egy for the synthesis of aminocyclohexitols 7 and 8. The starting
material 5-O-tert-butyl dimethylsilyl-2,3-O-isopropylidene-
furanose 9, which was required for our synthesis was prepared
from
-ribose using reported procedure (Scheme 1).16 The reaction
D-ribo-
D
of 9 with benzylamine gave ribosylamine; treatment of the crude
ribosylamine with allylbromide and zinc furnished amino alcohol
10 exclusively as a single isomer in 70% yield over two steps.11
The formation of erythro isomer 10 can be explained by nucleo-
philic addition onto the imine generated from the ribosalamine
of 9 via a seven membered transition state resulting from the che-
lation of hydroxyl and an imine, or a Felkin-Anh model, as per our
earlier observations.11 The secondary hydroxyl group of compound
10 was protected as its triethylsilyl ether to give 11 in 93% yield.
The amino functionality in 11 was converted into a carbamate with
CbzCl to give 12 in 85% yield. The hydroboration of olefin 12 gave
alcohol 13 in 85% yield. The primary alcohol in compound 13 was
oxidized with TEMPO/BAIB in CH2Cl2, to give aldehyde 13a which
upon treatment with Et3N/Eschenmoser’s salt17 in the same pot
leaving group oxygen atom in the a- or b-orientation in the transi-
tion state of a glycosidase catalyzed reaction.5 Recently, Ogawa and
co-workers reported the importance of NOV 5 and NOEV 6 in chap-
erone therapy.6 Tamiflu is also related to the aminocyclohexitols,
which is used in the treatment of bird flu.7 Due to the interesting
biological activity and structural features, there has been a remark-
able growth in the design, synthesis, and evaluation of new amino-
cyclohexitols as glycosidase inhibitors.8,9
yielded the
ried through to the next step immediately without any purifica-
tion. Reduction of the crude -methylene aldehyde 13b under
a-methylene aldehyde 13b. Compound 13b was car-
a
Luche conditions at ꢀ78 °C in methanol gave allylic alcohol 14 in
75% yield from 13. Allylic alcohol 14 was protected as the MOM–
ether to provide 15 in 94% yield. Deprotection of the silyl groups
in 15 with TBAF furnished diol 16 in 93% yield. The 1,2-diol func-
tionality in compound 16 was converted into olefin 17 in 75% yield
by using Garreg’s protocol.18
Ring closing metathesis of diene 17 with 10 mol % Grubbs II
generation catalyst15 in toluene at reflux gave aminocyclohexene
18 in 85% yield. The stereoselective hydroboration of aminocyclo-
hexene 18 yielded the hydroxyl compound 19 in 68% yield. Dihydr-
oxylation of 18 gave diol 20 in 80% yield. Hydrogenation of 19 and
20 using Pd/C under acidic conditions yielded carbamannopyrano-
In continuation of our efforts in the area of ‘carbohydrate mim-
ics’ such as carbasugars,10 aminocarbasugars,11 and iminosugars,12
we herein report the stereoselective synthesis of carbamannopyr-
anosylamine 713 and valiolamine analogue 8.14 In our previous
communication, we reported an RCM15 based approach for the
synthesis of N-benzyl aminocyclopentitols,11 where we utilized
Eschenmoser’s salt for the efficient preparation of a diene precur-
⇑
Corresponding author. Tel./fax: +91 40 27193003.
E-mail addresses: venky@iict.res.in, drb.venky@gmail.com (B.V. Rao).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.07.009

A. Rajender et al. / Tetrahedron: Asymmetry 22 (2011) 1306–1311
1307
OH
OH
OH
OH
HO
HO
HO
HO
HO
HO
HO
HO
HO
HO
OH
OH
OH
NH2
NH2
OH
NH2
N
H
OH
OH
OH
OH
4
1
3
2
OH
OH
HO
HO
HO
HO
NH(CH2)7CH3 HO
HO
HO
HO
HO
4
4
NH(CH2)7CH3
NH2
NH2
OH
OH
OH
OH
5
8
7
6
Figure 1.
sylamine 7 and (1S,2S)-valiolamine 8, respectively. The crude mix-
ture of 7 and 8 upon acetylation afforded peracetyl derivatives 21
and 22 in 80% yield over two steps. The physical and spectroscopic
data of 2113 and 2214 were in good agreement with the reported
values (Scheme 2).
4. Experimental
4.1. General
TLC was performed on Merck Kiesel gel 60, F254 plates (layer
thickness 0.25 mm). Column chromatography was performed on
silica gel (60–120 mesh) using ethyl acetate and hexane mixture
as the eluent. Melting points were determined on a Fisher John’s
melting point apparatus and are uncorrected. IR spectra were
recorded on a Perkin–Elmer RX-1 FT-IR system. 1H NMR and 13C
NMR spectra were recorded using Varian Gemini-200 MHz and
400 MHz or a Bruker Avance-300 MHz spectrometer. 1H NMR data
3. Conclusions
In conclusion, we have successfully reported the application of
our strategy for the synthesis of aminocyclohexitols using RCM.
Further studies of the applications of this strategy for the synthesis
of more complex systems are currently in progress.
TBSO
NHBn
O
NHBn
O
OH
OH
TESO
TBSO
ii
ref.16
i
TBSO
TBSO
D-ribose
O
O
O
O
O
11
Cbz
NBn
9
10
Cbz
Cbz
TBSO
TESO
TBSO
TESO
NBn
NBn
TESO
OH
iii
iv
v(a)
CHO
O
O
O
O
O
O
13a
13
Cbz
NBn
Cbz
Cbz
TBSO
TESO
TBSO
TESO
TBSO
NBn
NBn
OMOM
v(b)
v(c)
OH
TESO
vi
CHO
O
O
O
O
O
O
13b
15
14
Cbz
NBn
Cbz
HO
NBn
vii
OMOM
OMOM
HO
viii
O
O
O
O
17
16
Scheme 1. Reagents and conditions: (i) (a) BnNH2, MeOH, reflux, overnight; (b) allylbromide, Zn, THF, 0 °C to rt, 12 h, 70% (over two steps); (ii) TES-Cl, imidazole, cat. DMAP,
CH2Cl2, 0 °C, 10 min, 93%; (iii) NaH, CbzCl, THF, 0 °C, 1 h, 85%; (iv) BH3.DMS, THF, 0 °C, 2 h, NaOH, H2O2, 0 °C, 85%; (v) (a) TEMPO, BAIB, CH2Cl2, 0 °C, 2 h; (b) Et3N,
Eschenmoser’s salt, rt, 4 h; (c) NaBH4, CeCl3ꢁ7H2O, MeOH, ꢀ78 °C, 30 min, 75% (from 13); (vi) MOM–Cl, DIPEA, cat. DMAP, CH2Cl2, 0 °C, 94%; (vii) TBAF, THF, rt, 1 h, 93%, (viii)
TPP, I2, imidazole, toluene, reflux, 4 h, 75%.

1308
A. Rajender et al. / Tetrahedron: Asymmetry 22 (2011) 1306–1311
OMOM
OAc
HO
AcO
AcO
iv
ii
O
NBn
Cbz
NHAc
OAc
OMOM
O
OAc
21
19
i
17
OMOM
O
NBn
Cbz
HO
O
HO
AcO
HO
iv
iii
18
O
NBn
Cbz
AcO
NHAc
O
OAc
22
20
Scheme 2. Reagents and conditions: (i) 10 mol % Grubbs second generation catalyst, toluene, reflux, 12 h, 85%; (ii) BH3ꢁDMS, H2O2, NaOH, THF, 0 °C, 3 h, 68%; (iii) OsO4, NMO,
acetone/water, 4:1, rt, 3 h, 80%; (iv) (a) 10% Pd/C, H2, concd HCl, rt, 12 h; (b) Ac2O, pyridine, cat. DMAP, rt, 12 h, 80% (over two steps).
are expressed as chemical shifts in ppm followed by multiplicity
(s–singlet; d–doublet; t–triplet; q–quartet; m–multiplet), number
of proton(s) and coupling constant(s) J (Hz). 13C NMR chemical
shifts are expressed in ppm. Optical rotations were measured with
JASCO digital polarimeter. Accurate mass measurement was per-
formed on Q STAR mass spectrometer (Applied Biosystems, USA).
red for 10 min. The reaction mixture was extracted in CH2Cl2
(100 mL) and washed with brine. The organic layer was separated,
dried over anhydrous Na2SO4, concentrated, purified by column
chromatography using hexane/ethyl acetate (19:1) to give 11
(5.30 g, 93%) as a syrup. ½a D25
ꢃ
¼ þ24:1 (c 2.4, CHCl3); IR (neat) mmax
2978, 1698, 1385, 1083 cmꢀ1
;
1H NMR (CDCl3, 300 MHz): d 0.02–
0.08 (m, 6H), 0.52–0.65 (m, 6H), 0.86–0.95 (m, 18H), 1.30 (s, 3H),
1.41 (s, 3H), 2.25–2.48 (m, 2H), 2.92–3.03 (m, 1H), 3.64 (dd, 1H,
J = 5.2, 10.7 Hz), 3.72 (d, 1H, J = 12.4 Hz), 3.75–3.87 (m, 2H), 3.95–
40 (m, 1H), 4.08–4.22 (m, 2H), 5.03–5.15 (m, 2H), 5.81–5.96 (m,
1H), 7.16–7.32 (m, 5H); 13C NMR (CDCl3, 75 MHz): ꢀ5.4, ꢀ5.5,
5.0, 6.9, 18.3, 24.6, 25.7, 26.3, 34.5, 50.7, 55.7, 66.0, 73.3, 77.0,
78.8, 107.4, 117.7, 126.7, 127.9, 128.1, 134.8, 140.4; ESI/MS (m/
z): 550 (M+H)+; HRMS Calcd for C30H56NO4Si2 (M+H)+ 550.3747.
Found: 550.3722.
4.2. (R)-1-((4R,5S)-5-((S)-1-(Benzylamino)-but-3-enyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)-2-(tert-but-yldimethylsilyloxy )
ethanol 10
To a stirred solution of ribofuranose 9 (10 g, 32.89 mmol) in dry
MeOH (100 mL), 4 Å molecular sieves, Na2SO4, and BnNH2 (8.9 mL,
82.23 mmol) were added at rt. The reaction mixture was refluxed
overnight. The reaction mixture was filtered on a Celite pad and
the solvent was evaporated under reduced pressure. To this crude
lactamine (12.9 g, 32.89 mmol) in dry THF (120 mL), at ꢀ15 °C,
allylbromide (41.6 mL, 493.42 mmol) was added and then Zn
(27.86 g, 426.71 mmol) was added portionwise over a period of
15 min at 0 °C. After stirring overnight at room temperature, the
reaction mixture was quenched with a saturated NH4Cl solution
and filtered on a Celite pad. The filtrate was extracted into ethyl-
acetate (3 ꢂ 100 mL). The collected organic layers were combined,
washed with aq 1 M HCl, separated then dried over Na2SO4, con-
centrated under reduced pressure, and purified through column
chromatography on silica gel using hexane/ethyl acetate (9:1) to
afford the corresponding amino alcohol 10 as a colorless oil
4.4. Benzyl benzyl((S)-1-((4S,5S)-5-((R)-3,3-diethyl-8,8,9,9-tetra
methyl-4,7-dioxa-3,8-disiladecan-5-yl)-2,2-dimethyl-1,3-dioxo
lan-4-yl)but-3-enyl)carbamate 12
To an ice cooled, stirred solution of compound 11 (5.0 g,
9.10 mmol) in dry THF, NaH (0.72 g, 60% w/v dispersion in mineral
oil, 18.2 mmol) and Cbz-Cl (3.88 mL, 50% in toluene, 13.6 mmol)
were added and the reaction mixture was stirred at room temper-
ature for 1 h. The reaction mixture was quenched with a saturated
NH4Cl solution and extracted with ethyl acetate (2 ꢂ 100 mL). The
combined organic layers were washed with brine, separated and
then dried over anhydrous Na2SO4, and concentrated under re-
duced pressure. The crude material was purified by column chro-
matography on silica gel by eluting with hexane/ethyl acetate
(19:1) to give compound 12 (5.50 g, 85% yield) as a syrup.
(10.0 g, 70% over two steps). ½a D25
ꢃ
¼ þ11:5 (c 1.9, CHCl3); IR (neat)
mmax 3445, 3071, 2929, 1637, 1070 cmꢀ1
;
1H NMR (CDCl3,
300 MHz): d 0.10 (s, 6H), 0.93 (s, 9H), 1.32 (s, 3H), 1.40 (s, 3H),
2.50–2.68 (m, 2H), 3.03–3.13 (m, 1H), 3.61–3.73 (m, 2H), 3.76
(dd, 1H, J = 4.5, 10.7 Hz); 3.82–3.98 (m, 3H), 4.19–4.30 (m, 1H),
5.18–5.28 (m, 2H), 5.76–5.96 (m, 1H), 7.21–7.38 (m, 5H); 13C
NMR (CDCl3, 75 MHz): -5.2, -5.3, 18.5, 25.6, 26.0, 28.1, 32.4, 50.4,
54.9, 65.0, 69.5, 77.1, 77.6, 108.2, 119.7, 127.5, 128.7, 133.0,
138.0; ESI/MS (m/z): 436 (M+H)+; HRMS Calcd for C24H42NO4Si
(M+H)+ 436.2883. Found: 436.2867.
½
a 2D5
ꢃ
¼ þ5:4 (c 0.19, CHCl3); IR (neat) mmax 2949, 2880, 1699,
1458, 1375, 1250, 1099 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 0.01–
;
0.10 (m, 6H), 0.53–0.74 (m, 6H), 0.82–1.02 (m, 18H), 1.16 (s, 3H),
1.40 (s, 3H), 2.16–2.49 (m, 2H), 3.54–4.02 (m, 3H), 4.04–4.19 (m,
1H); 4.21–4.32 (m, 1H), 4.45–5.20 (m, 7H), 5.46–5.88 (m, 1H),
7.01–7.40 (m, 10H) (1H NMR Spectra not resolved clearly due to
rotameric mixture); 13C NMR (CDCl3, 75 MHz): ꢀ5.5, 5.1, 6.9,
18.4, 24.5, 26.1, 34.1, 46.7, 47.0, 55.6, 55.8, 65.1, 66.9, 67.3, 72.4,
77.1, 78.8, 79.3, 107.6, 116.5, 116.8, 126.4, 126.5, 127.1, 127.5,
127.7, 127.9, 125.1, 128.4, 135.4, 135.5, 136.6, 139.8, 140.0,
156.8, 157.0 (multiple peaks in the spectra are due to rotameric
mixture); ESI/MS (m/z): 684 (M+H)+; HRMS Calcd for C38H61NO6
Si2Na (M+Na)+ 706.3930. Found: 706.3935.
4.3. (S)-N-Benzyl-1-((4S,5S)-5-((R)-3,3-diethyl-8,8,9,9-tetrameth
yl-4,7-dioxa-3,8disiladecan -5-yl)-2,2-dimethyl-1,3-dioxolan-4-
yl)but-3-en-1-amine 11
To an ice cooled stirred solution of amino alcohol 10 (4.50 g,
10.35 mmol) in dry CH2Cl2 (50 mL) was added imidazole (2.8 g,
41.4 mmol) and triethylsilylchloride (3.5 mL, 20.6 mmol) and stir-

A. Rajender et al. / Tetrahedron: Asymmetry 22 (2011) 1306–1311
1309
4.5. Benzyl benzyl((S)-1-((4S,5S)-5-((R)-3,3-diethyl-8,8,9,9-tet
ramethyl-4,7-dioxa-3,8-disiladecan-5-yl)-2,2-dimethyl-1,3-dio
xolan-4-yl)-4-hydroxybutyl)carbamate 13
(multiple peaks in the spectra are due to a rotameric mixture);
ESI/MS (m/z): 714 (M+H)+; HRMS Calcd for C39H64NO7Si2 (M+H)+
714.4223. Found: 714.4221.
To the stirred solution of 12 (1.30 g, 1.90 mmol) in dry THF
(10 mL), BH3.Me2S (0.39 mL, 4.18 mmol) was added dropwise at
ꢀ10 °C. Stirring was continued for 3 h at room temperature. The
reaction mixture was quenched by the addition of 10% NaOH
(10 mL) followed by 30% H2O2 (15 mL) at 0 °C and allowed to warm
to room temperature, and stirred for another 2 h. The reaction mix-
ture was extracted with ethyl acetate (2 ꢂ 100 mL). The combined
organic layers were washed with brine, separated and dried over
anhydrous Na2SO4, the solvent was removed on rotary evaporator.
The residue was purified by column chromatography on silica gel
using hexane/ethyl acetate (4.5:0.5) as the eluant to give pure
4.7. Benzyl benzyl((S)-1-((4S,5S)-5-((R)-3,3-diethyl-8,8,9,9-tetra
methyl-4,7-dioxa-3,8-disila-decan-5-yl)-2,2-dimethyl-1,3-dioxo
lan-4-yl)-4-(methoxymethoxy)methyl)but-3-enyl)carbamate 15
To an ice cooled, stirred solution of alcohol 14 (0.50 g, 0.7 mmol)
in CH2Cl2 (20 mL) were added DIPEA (0.48 mL, 2.8 mmol), MOM–Cl
(0.17 mL, 2.1 mmol), and DMAP (cat). The reaction mixture was al-
lowed to warm at room temperature and then stirred for 12 h. The
reaction mixture was then extracted with CH2Cl2 (3 ꢂ 30 mL). The
combined organic layers were washed with brine, separated and
dried over anhydrous Na2SO4 and the solvent was concentrated un-
der reduced pressure. The crude product was purified by column
chromatography using hexane/ethyl acetate (9:1) to afford com-
compound 13 (1.13 g, 85%) as a syrup. ½a D25
¼ ꢀ32:5 (c 1.87,
ꢃ
CHCl3); IR (neat) mmax 3435, 2948, 2878, 1695, 1458, 1414, 1375,
1252, 1098, 1006, 835, 734 cmꢀ1
;
1H NMR (CDCl3, 300 MHz): d
pound 15 (0.50 g, 94%) as a yellow oil. ½a D25
¼ ꢀ19:9 (c 1.67, CHCl3);
ꢃ
0.10–0.0.10 (m, 6H), 0.53–0.78 (m, 6H), 0.89 (s, 9H), 0.89–1.01
(m, 9H), 1.20 (s, 3H), 1.08–1.58 (m, 2H), 1.41 (s, 3H), 1.44–1.69
(m, 2H), 3.11–3.52 (m, 2H), 3.52–4.01 (m, 3H); 4.06–4.32 (m,
2H), 4.51–4.78 (m, 3H), 4.94–5.51 (m, 2H), 7.14–7.45 (m, 10H);
13C NMR (CDCl3, 75 MHz): ꢀ5.5, 5.1, 6.9, 18.3, 24.5, 25.6, 25.8,
26.0, 29.1, 46.6, 56.0, 62.6, 65.1, 67.2, 72.4, 77.2, 79.6, 107.6,
126.6, 127.3, 127.7, 127.9, 128.0, 128.2, 128.3, 136.5, 136.6,
140.0, 156.9; ESI/MS (m/z): 702 (M+H)+; HRMS Calcd for
IR (neat) m
max 2922, 2856, 1699, 1253, 1103, 838, 738, 692 cmꢀ1; 1H
NMR (CDCl3, 300 MHz): d 0.00–0.10 (m, 6H), 0.53–0.76 (m, 6H),
0.84–1.0 (m, 18H), 1.20 (s, 3H), 1.42 (s, 3H), 2.11–2.44 (m, 2H),
3.24–3.37 (m, 3H), 3.44–4.24 (m, 5H), 4.30 (d, 1H, J = 7.1 Hz), 4.39–
4.90 (m, 5H), 4.88–5.15 (m, 3H), 7.04–7.43 (m, 10H) (multiple peaks
in the spectra are due to a rotameric mixture); 13C NMR (CDCl3,
75 MHz): ꢀ5.7, 3.9, 5.0, 6.5, 6.7, 18.1, 24.3, 25.6, 32.4, 46.3, 46.8,
53.3, 53.7, 54.8, 64.5, 64.9, 66.6, 67.1, 69.4, 69.7, 71.9, 76.3, 76.8,
79.2, 79.7, 95.0, 107.5, 112.9, 113.9, 126.1, 126.8, 127.4, 127.7,
127.8, 128.0, 128.5, 136.2, 139.5, 139.7, 141.4, 142.0, 156.4, 156.8
(doubling of peaks in the spectra due to rotameric mixture); ESI/
MS (m/z): 758 (M+H)+; HRMS Calcd for C41H67NO8Si2Na (M+Na)+
780.4311. Found: 780.4302.
C
38H63NO7Si2Na (M+Na)+ 724.4041. Found: 724.4040.
4.6. Benzyl benzyl((S)-1-((4S,5S)-5-((R)-3,3-diethyl-8,8,9,9-tet
ramethyl-4,7-dioxa-3,8-disila-decan-5-yl)-2,2-dimethyl-1,3-
dioxolan-4-yl)-3-(hydroxymethyl)but-3-enyl)carbamate 14
To an ice cooled stirred solution of alcohol 13 (1.0 g, 1.42 mmol)
in CH2Cl2 (10 mL), TEMPO (0.02 g, 0.14 mmol) and BAIB (1.10 g,
2.84 mmol) were added. The reaction mixture was stirred at room
temperature for 5 h. After conversion, the aldehyde, triethylamine
(0.8 mL, 5.7 mmol), and Eschenmoser’s salt (0.6 g, 3.2 mmol) were
added at rt. The reaction mixture was stirred for another 3 h and
extracted with CH2Cl2 (2 ꢂ 50 mL). The organic layer was washed
with brine, separated, and dried over anhydrous Na2SO4. The sol-
vent was removed on a rotary evaporator and the crude product
aldehyde was taken to the next reaction.
4.8. Benzyl benzyl((S)-1-((4S,5R)-5-((R)-1,2-dihydroxyethyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)-4-(methoxymethoxy)methyl)but-
3-enyl)carbamate 16
To a stirred solution of compound 15 (0.4 g, 0.52 mmol) in dry
THF (7 mL) was added a 1 M solution of TBAF (1.5 mL, 1.58 mmol)
at room temperature and stirred for 1 h. The solvent was removed
on a rotary evaporator and the residue was purified by column
chromatography on silica gel using hexane/ethyl acetate (1:1) as
the eluant to give pure compound diol 16 (0.26 g, 93%) as a color-
To an ice cooled, stirred solution of CeCl3ꢁ7H2O (1.0 g,
2.81 mmol) in MeOH (15 mL), NaBH4 (0.21 g, 5.6 mmol) was added
portionwise. After being stirred at 0 °C for 10 min, the reaction
mixture was further cooled to ꢀ78 °C. To it, the above crude alde-
hyde in MeOH (10 mL) was added. The reaction mixture was stir-
red for another 30 min at ꢀ78 °C. To this reaction mixture
saturated NaHCO3 solution was added, after which the solvent
was removed under reduced pressure. The residue was taken in
ethyl acetate, and filtered through a Celite pad. The filtrate was
washed with brine, separated, and the combined organic layers
were removed on a rotary evaporator. The residue was purified
by column chromatography on silica gel using hexane/ethyl ace-
tate (9:1) as the eluant to give pure compound 14 (0.76 g, 75% over
less liquid. ½a 2D5
ꢃ
¼ þ0:9 (c 1.97, CHCl3); IR (neat) mmax 3405, 2921,
2852, 1676, 1211, 1051, 910, 735, 697 cmꢀ1
;
1H NMR (CDCl3,
300 MHz): d 1.10 (s, 3H), 1.38 (s, 3H), 2.44 (d, 2H, J = 7.1 Hz),
3.35 (s, 3H), 3.50 (dd, 1H, J = 2.6, 8.3 Hz), 3.71 (dd, 1H, J = 2.6,
8.3 Hz), 3.79–3.96 (m, 2H), 4.02–4.25 (m, 2H), 4.40 (d, 1H,
J = 15.8 Hz), 4.52–4.69 (m, 2H), 4.75–4.97 (m, 1H), 4.99–5.16 (m,
3H), 7.04–7.43 (m, 10H) (multiple peaks in the spectra are due to
a rotameric mixture); 13C NMR (CDCl3, 75 MHz): 24.7, 27.0, 32.9,
46.2, 52.6, 55.4, 64.8, 67.6, 68.8, 69.5, 78.0, 78.7, 95.4, 108.1,
115.3, 126.9, 127.8, 127.9, 128.2, 136.1, 138.7, 141.9, 157.8; ESI/
MS (m/z): 530 (M+H)+; HRMS Calcd for C29H39NO8Na (M+Na)+
552.2560. Found: 552.2573.
two steps) as a colorless liquid. ½a D25
ꢃ
¼ ꢀ21:1 (c 2.44, CHCl3); IR
4.9. Benzyl benzyl((S)-1-((4S,5R)-2,2-dimethyl-5-vinyl-1,3-diox
olan-4-yl)-3((methoxy methoxy)methyl)but-3-enyl)carbamate
17
(neat) mmax 3400, 2945, 2877, 1686, 1252, 1209, 1100, 996, 903,
837, 736 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 0.02–0.08 (m, 6H),
;
0.58–0.72 (m, 6H), 0.88–0.97 (m, 18H), 1.19 (s, 3H), 1.43 (s, 3H),
2.07 (d, 1H, J = 13.9 Hz), 2.42 (dd, 1H, J = 2.2, 13.9 Hz), 3.66–3.75
(m, 1H), 3.78–3.88 (m, 1H), 3.93 (s, 2H), 4.01–4.09 (m, 1H), 4.14
(dd, 1H, J = 6.7, 14.7 Hz), 4.23 (br d, 1H, J = 7.1 Hz), 4.46–4.67 (m,
3H), 4.79 (br s, 1H), 4.90–4.92 (m, 1H), 5.03 (s, 2H), 7.04–7.39
(m, 10H); 13C NMR (CDCl3, 75 MHz): ꢀ5.7, 5.0, 6.7, 18.1, 24.3,
25.6, 33.8, 46.2, 54.5, 64.9, 66.2, 66.9, 72.0, 76.8, 78.5, 107.7,
112.7, 126.7, 127.4, 127.7, 127.8, 128.7, 136.1, 139.4, 145.8, 157.0
To a stirred solution of diol 16 (0.20 g, 0.37 mmol) in dry tolu-
ene (8 mL) were added triphenylphosphine (0.40 g, 1.5 mmol),
and imidazole (0.10 g, 1.5 mmol) at room temperature, after which
it was heated to 60 °C. Next, iodine (0.14 g, 1.13 mmol) was added
in small portions. The reaction was further heated at reflux for 4 h.
The reaction mixture was quenched with an excess Na2S3O3 solu-
tion and extracted into ethyl acetate (2 ꢂ 25 mL). The combined

1310
A. Rajender et al. / Tetrahedron: Asymmetry 22 (2011) 1306–1311
organic layers were washed with brine, separated and dried over
anhydrous Na2SO4, and the solvent was concentrated under re-
duced pressure. The crude product was purified by column chro-
matography using elutant hexane/ethyl acetate (9:1) to afford
4.12. Benzyl benzyl((3aS,4S,6R,7R,7aR)-6,7-dihydroxy-6-((meth
oxymethoxy)methyl)-2,2-dimethyl-hexahydrobenzo[d][1,3]dio
xol-4-yl)carbamate 20
olefin 17 (0.14 g, 75%) as a pale yellow liquid. ½a D25
ꢃ
¼ þ13:7 (c
To an ice cooled, stirred solution of compound 18 (0.10 g,
0.21 mmol) in acetone/water (4:1) (2 mL) were added NMO
(0.043 g, 0.32 mmol) and OsO4 (0.25 g in 20 mL toluene)
(0.43 mL, 0.02 mmol). The reaction was allowed to return to room
temperature and stirred for another 3 h. The reaction mixture was
quenched with solid Na2S2O3. The solvent was removed under re-
duced pressure and extracted with ethyl acetate (2 ꢂ 25 mL). The
combined organic extracts were washed with brine, separated,
and dried over anhydrous Na2SO4. The solvent was removed on a
rotary evaporator and the residue was purified by column chroma-
tography on silica gel using hexane/ethyl acetate (1:1) as the elu-
ant to give pure compound 20 (0.08 g, 80%) as a colorless liquid.
1.86, CHCl3); IR (neat) mmax 2985, 2935, 1694, 1452, 1415, 1245,
1213, 1046, 739, 698 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 1.20 (s,
;
3H), 1.38 (s, 3H), 2.46–2.48 (m, 2H), 3.33–3.35 (m, 3H), 3.63–
4.03 (m, 2H), 4.08–4.40 (m, 2H), 4.49–4.61 (m, 2H), 4.55–4.68
(m, 1H), 4.73–4.91 (m, 1H), 4.96–5.32 (m, 5H), 5.64–5.96 (m,
1H), 7.13–7.41 (m, 10H) (spectra not resolved clearly due to a rota-
meric mixture); 13C NMR (CDCl3, 75 MHz): 24.7, 27.0, 32.2, 46.8,
53.9, 55.2, 67.2, 67.5, 69.3, 69.6, 78.9, 79.0, 79.9, 95.4, 95.5,
108.3, 114.2, 115.0, 118.7, 119.0, 126.9, 127.2, 127.4, 128.1,
128.3, 128.4, 133.5, 133.8, 139.0, 142.1 (doubling of peaks in the
spectra are due to a rotameric mixture); ESI/MS (m/z): 496
(M+H)+; HRMS Calcd for C29H37NO6Na (M+Na)+ 518.2493. Found:
518.2518.
½
a 2D5
ꢃ
¼ ꢀ4:6 (c 1.33, CHCl3); IR (neat) mmax 1430, 2922, 2854,
1697, 1458, 1245, 1045, 966 cmꢀ1 1H NMR (CDCl3, 300 MHz): d
;
1.15 (s, 3H), 1.50 (s, 3H), 1.54–1.68 (m, 1H), 1.86 (t, 1H,
J = 13.6 Hz), 2.75–3.07 (m, 2H), 3.19 (s, 3H), 3.46 (s, 2H), 3.54 (d,
1H, J = 6.7 Hz), 3.97–4.16 (m, 1H), 4.23–4.43 (m, 1H), 4.54 (s, 2H),
4.68–4.93 (m, 2H), 4.93–5.38 (m, 3H), 7.01–7.46 (m, 10H) (multi-
ple peaks in the spectra are due to rotameric mixture); 13C NMR
(CDCl3, 75 MHz): 25.9, 28.4, 31.3, 47.8, 47.9, 49.1, 55.3, 67.3,
73.0, 73.5, 73.8, 76.1, 80.5, 96.7, 109.6, 126.0, 126.3, 127.7, 128.2,
139.9, 156.7; ESI/MS (m/z): 502 (M+H)+; HRMS Calcd for
4.10. Benzyl benzyl((3aS,4S,7aR)-6-((methoxymethoxy)methyl)-
2,2-dimethyl-3a,4,5,7a-tetrahydrobenzo[d][1,3]dioxol-4-yl)car
bamate 18
To a solution of diene 17 (0.10 g, 0.20 mmol) in toluene (25 mL),
Grubbs second generation catalyst (0.018 g, 0.02 mmol) was added
at rt. The reaction mixture was refluxed for 12 h. Toluene was re-
moved under reduced pressure and the crude mixture was purified
by column chromatography using hexane/ethyl acetate (7:3) as
elutant to provide aminocyclohexene 18 (0.08 g, 85%) as an oil.
C
27H36NO8 (M+H)+ 502.2416. Found: 502.2440.
4.13. (1S,2R,3S,4S,6S)-4-Acetamido-6-(acetoxymethyl)cyclohexa
ne-1,2,3-triyl triacetate 21
½
a 2D5
ꢃ
¼ ꢀ23:2 (c 0.5, CHCl3); IR (neat) mmax 2961, 1696, 1455,
1371, 1227, 1106, 1033, 859, 737, 699 cmꢀ1 1H NMR (CDCl3,
;
To a solution of 19 (0.02 g, 0.04 mmol) in MeOH (2 mL) was
added concentrated HCl (0.2 mL) and 10% Pd/C (cat), after which
the reaction mixture was hydrogenated overnight at rt. The reac-
tion mixture was filtered through a Celite pad, the solvent was
evaporated after which pyridine (2 mL), Ac2O (0.1 mL), and cata-
lytic amount of DMAP were added at rt and stirred overnight.
The solvent was removed under reduced pressure. The crude prod-
uct was purified by column chromatography with 5% MeOH in
CHCl3 to afford pentaacetate 21 (0.012 g, 80% over two steps) as
300 MHz): d 1.19 (s, 3H), 1.32 (s, 3H), 1.96 (dd, 1H, J = 3.0,
13.9 Hz), 2.35 (dd, 1H, J = 13.9 Hz), 3.28 (s, 3H), 3.89 (s, 2H),
4.25–4.36 (m, 1H), 4.46–4.84 (m, 6H), 5.07–5.29 (m, 2H), 5.48–
5.60 (m, 1H), 7.09–7.42 (m, 10H); 13C NMR (CDCl3, 75 MHz):
24.9, 26.5, 27.9, 47.3, 52.9, 55.2, 67.4, 69.9, 74.6, 75.3, 95.4,
109.7, 122.7, 126.3, 126.4, 126.8, 127.8, 128.0, 128.2, 135.6,
139.8, 156.7; ESI/MS (m/z): 468 (M+H)+; HRMS Calcd for
C
27H33NO6Na (M+Na)+ 490.2207. Found: 490.2205.
a white solid. mp 175–178 °C; ½a D25
¼ ꢀ14:7 (c 0.54, CHCl3); IR
ꢃ
4.11. Benzyl benzyl((3aS,4S,6S,7S,7aR)-7-hydroxy-6-((methoxy
methoxy)methyl)-2,2-dimethyl-hexahydrobenzo[d][1,3]dioxol-
4-yl)carbamate 19
(neat) mmax 3370, 2923, 1742, 1657, 1541, 1371, 1228, 1047,
958 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 1.56–1.63 (m, 1H), 1.96
;
(s, 6H), 1.97–2.10 (m, 2H), 2.04 (s, 3H), 2.06 (s, 3H), 2.21 (s, 3H),
3.98 (dd, 1H, J = 3.7, 11.0 Hz), 4.05 (dd, 1H, J = 6.0, 11.0 Hz), 4.27
(m, 1H), 4.94 (dd, 1H, J = 2.6, 10.2 Hz), 5.18 (t, 1H, J = 10.2 Hz),
5.45 (t, 1H, J = 2.6 Hz), 5.49 (d, 1H, J = 8.6 Hz); 13C NMR (CDCl3,
75 MHz): 20.5, 20.7, 23.2, 28.7, 37.9, 46.7, 63.7, 68.9, 71.5, 72.6,
169.2, 169.7, 170.1, 170.3, 170.7; ESI/MS (m/z): 386 (M+H)+; HRMS
Calcd for C17H25NO9Na (M+Na)+ 410.1410. Found: 410.1427.
To a solution of 18 (0.10 g, 0.21 mmol) in THF (4 mL), BH3ꢁMe2S
(0.04 mL, 0.47 mmol) was added dropwise at ꢀ10 °C. Stirring was
continued for 30 min at room temperature. The reaction mixture
was quenched by the addition of 10% NaOH (1 mL) followed by
30% H2O2 (2 mL) at 0 °C. The mixture was allowed to warm at room
temperature and stirred for another 2 h. The reaction mixture was
extracted with ethyl acetate (2 ꢂ 20 mL) and the combined organic
extracts were washed with brine, separated, and dried over anhy-
drous Na2SO4. The solvent was removed on a rotary evaporator and
the residue was purified by column chromatography on silica gel
using hexane/ethyl acetate (1:1) as the eluant to give pure com-
4.14. (1S,2S,3R,4R,6S)-6-Acetamido-4-(acetoxymethyl)-4-
hydroxycyclohexane-1,2,3-triyl triacetate 22
To a solution of 20 (0.02 g, 0.039 mmol) in MeOH (4 mL) was
added concentrated HCl (0.2 mL) and 10% Pd/C (cat), the reaction
mixture was hydrogenated overnight at rt. The reaction mixture
was filtered through celite pad, the solvent was evaporated under
reduced pressure. To this crude product, pyridine (2 mL), Ac2O
(0.1 mL), a catalytic amount of DMAP were added at rt, and then
stirred overnight. The solvent was removed under reduced pres-
sure, the crude product was purified by column chromatography
with 5% MeOH in CHCl3 as an elutant to afford penta acetate 22
(0.015 g, 80% over two steps) as a white solid. mp 265–269 °C;
pound 19 (0.07 g, 68%) as a colorless liquid. ½a D25
¼ ꢀ32:5 (c 1.87,
ꢃ
CHCl3); IR (neat) mmax 3422, 2925, 1692, 1455, 1244, 1042,
698 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 1.23 (s, 3H), 1.50 (s, 3H),
;
1.59–1.75 (m, 3H), 2.86 (br s, 1H), 3.22 (s, 3H), 3.50–3.59 (m,
3H), 3.85–3.96 (m, 1H), 4.28–4.42 (m, 1H), 4.54 (s, 3H), 4.66–
4.77 (m, 2H), 5.10–5.31 (m, 2H), 7.05–7.43 (m, 10H); 13C NMR
(CDCl3, 75 MHz): 26.0, 26.5, 25.5, 29.6, 39.9, 47.7, 53.2, 55.2,
67.4, 69.2, 74.3, 76.4, 82.0, 96.4, 109.9, 126.1, 126.3, 126.4, 127.8,
128.1, 139.9, 156.8; ESI/MS (m/z): 486 (M+H)+; HRMS Calcd for
½
a 2D5
ꢃ
¼ þ19:6 (c 0.61, CHCl3) {lit.,13
½
a 2D2
ꢃ
of enantiomer ¼ ꢀ15:6
C
27H35NO7Na (M+Na)+ 508.2297. Found: 508.2311.
(c 0.6, CHCl3)}; IR (neat) mmax 3371, 1743, 1650, 1540, 1459,

A. Rajender et al. / Tetrahedron: Asymmetry 22 (2011) 1306–1311
1311
1373, 1229, 1053 cmꢀ1; 1H NMR (CDCl3, 500 MHz): d 1.78 (dd, 1H,
J = 4.4, 13.2 Hz), 1.96 (s, 6H), 2.03 (dd, 1H, J = 4.4, 13.2 Hz), 2.09 (s,
6H), 2.20 (s, 3H), 2.70 (br s, 1H), 4.00 (ABq, 2H, J = 11.7 Hz), 4.62–
4.70 (m, 1H), 5.27 (d, 1H, J = 10.2 Hz), 5.35 (dd, 1H, J = 2.9,
10.2 Hz), 5.44 (d, 1H, J = 8.3 Hz), 5.50 (br s, 1H); 13C NMR (CDCl3,
75 MHz): 20.5, 20.7, 20.74, 21.0, 23.2, 34.0, 43.6, 67.3, 69.9, 70.2,
71.5, 71.9, 169.2, 169.7, 169.9, 170.3, 170.5; ESI/MS (m/z): 426
(M+Na)+; HRMS Calcd for C17H26NO10 (M+H)+ 404.1537. Found:
404.1556.
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Acknowledgments
A.R. thanks UGC and J.P.R. thanks CSIR (New Delhi) for a fellow-
ship and we would like to thank Dr. J.S. Yadav for constant support
and encouragement; we also thank DST (SR/S1/OC-14/2007), New
Delhi for financial assistance.
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